The molecular mechanisms of signal transduction through the platelet- derived growth factor (PDGF) and its receptor (PDGFR) was studied using both empirical and theoretical methods. The receptor extracellular domains 2-3. 1-3 and 1-5 were expressed and purified for biochemical and biophysical studies. The N-terminal Src homology region 2 (SH2) domain of PI 3-kinase was shown to be a calcium binding protein. which changed conformation on calcium binding and associated with the alphaPDGFR in a calcium-dependent manner. The kinase insert (KI) domain of the PDGFR binds the SH2 domains of PI 3-kinase and GTPase activating protein (GAP) through a phosphotyrosine-dependent mechanism. The KI domain of the ~PDGFR was shown to bind to both calcium and zinc ions through a common shared site. Calcium ions changed the conformation of this domain. while zinc ions did not. Both cations increased the association of the PI 3- kinase N-SH2 domain with the alphaPDGFR. Further, the non-phosphorylated KI domain was effective in competing the phosphorylated PDGFR for binding the N-SH2 domain of PI-3 kinase and this effect was enhanced in the presence of calcium ions. Micro-injectiOn of this domain into Xenopus oocytes delayed maturation in the presence of insulin but had no effect in the presence of progesterone. This suggests that the KI domain is in a biologically active conformation. Signaling through the epidermal growth factor receptor (EGFR) activates a number of substrates which signal through p2l Ras. a small GTP binding protein. The SH3 domain of Eps8. a substrate of the EGFR is thought to act indirectly through this pathway via its SH3 domain. This domain was expressed. purified and crystalized for three-dimensional structural studies. Pleckstrin homology (PH) domains are about 110 residues in length which bind the beta gamma- subunits of a heterotrimeric G-protein complex. These proteins couple to G-protein coupled receptors. The PH domains of Dbl, 5051 and IRS-I were expressed and purified for structure/function studies.